Process for the preparation of delta1,3,5(10)-3,17-dihydroxy steroids



molecule, for example a 17-keto group,

United States Patent 3,415,853 PROCESS FOR THE PREPARATION OF A3,17-DIHYDROXY STEROIDS Pieter Modderman, Oss, Netherlands, assignor toOrganon Inc., West Orange, N.J., a corporation of New Jersey No Drawing.Filed Apr. 20, 1966, Ser. No. 543,814 Claims priority, applicationNetherlands, Apr. 28, 1965, 6505397 4 Claims. (Cl. 260-3974) ABSTRACT OFTHE DISCLOSURE A -3,17-dihydroxy steroids are prepared by treatment of aA -3'keto-1O-methyl-IZB-hydroxy steroid with an alkali metal in presenceof a polycyclic aromatic compound and an ethereal solvent, followed byacid conversion of the alkali metal salt of the corresponding steroid,including the step of converting the 17B-hydroxy group to a mixed acetaland ketal. The process enables the preparation of A-3-keto-17/3-hydroxy-androstadiene having an ether structure at the17-position.

The invention relates to an improved process for the preparation of A-3-hydroxy-steroids by treatment of a A -3-keto-10-methyl-steroid withan alkali metal in the presence of a polycyclic aromatic compound and anethereal solvent, followed by acid con-version of the alkali metal saltof the relative steroid.

It is known that in ring A aromatic steroids can be obtained if a A-3-keto-10- methyl-steroid is reacted with an anionic radical from amixture of an alkali metal and a polycyclic aromatic compound in anethereal solution. (e.g. British Patent 1,001,211 and correspondingpatents.)

According to the above patents the starting products may possess allkinds of substituents elsewhere in the preferably ketalised, or a 17fi-hydroxyl group, possibly converted into the tetrahydropyranyl-ether.

It has been found, however, that the yield of this process is greatlyinfluenced by the nature of these substituents. Starting, for instance,from the A -3-keto-17B-hydroxy-androstadiene, a mixture is obtained fromwhich the desired oestradiol is hard to isolate, its yield beingmoreover relatively low (about 15%).

Starting from a l7-ester of the A -3-keto-l7B-hydrclxyandrostadiene,there is also obtained only about 15% oestradiol.

Higher yields are obtained if the relative 17fi-hydrox-ysteroid is firstconverted into the tetrahydropyranyl-ether. But then, too, the yield ofoestradiol calculated on the A -3-keto-17fi-hydroxy-androstadieneamounts only to about 45%.

It has been found now that the yield of the present process applied tothe aromatisation of A -3-keto-l0- methyl-17,6-hydroxy-steroids isconsiderably increased if the l7fl-hydroxy-steroid is converted into amixed acetal or ketal obtained by the addition of the17/3-hydroxysteroid to a vinyl-ether of the formula:

in which X=an alkyl group with 1-6 carbon atoms, and

3,415,853 Patented Dec. 10, 1968 R R and R =hydrogen or an alkyl groupwith 1-6 carbon atoms.

in which Y=an alkyl group with 1-4 carbon atoms.

Starting, for example, from the A -3-keto-17fi-hydroxy-androstadiene,the desired oestradiol is obtained in a yield of at least calculated onthe free A -3-ketol7/3-hydroxy-androstadiene after conversion of thiscompound into the acetal or ketal described before.

Besides this most important and surprising increased yield, the presentprocess has a few more advantages over the known process. Firstly thevinylalkyl-ethers to be used in the formation of the acetal or ketal aremuch cheaper than the dihydropyran to be used in the preparation oftetrahydropyranyl-ethers. Secondly the IZB-hydroxyl acetals or kefialsderive-d from the above-mentioned vinylalkyl-others are generallyobtained in a higher yield than the tetrahydropyranyl-ethers; andthirdly the final products can be isolated more easily in a purecondition than those obtained if tetrahydropyranyl-ethers are applied.

The prepa-ra ion of the 17fi-h-ydroxy derivatives according to theinvention takes place by reacting the relative l7-hydroxy-steroid with avinylalkyl-ether in the presence of an acid catalyst, such asparatoluene sulphonic acid, benzene sulphonic acid, dinitro benzenesulphonic acid, hydrochloric acid or a Lewis acid, such asborotrifluoride or the etherate thereof.

The reaction may be performed in the presence of a solvent, such as anaromatic hydrocarbon, for instance benzene or toluene, an ether, ahalogenated hydrocarbon, such as chloroform or carbon tetrachloride, orpetroleumether. If desired, an inhibitor, such as hydroquinone, may beadded to avoid polymerisation of the vinyl-ether.

The present process also relates to the new derivatives of a A-3-kcto-l7B-hydroxy-androstadiene compound, of which the structure atcarbon atom 17 is given below:

in which X, R R and R have the meaning indicated above, and R=hydrogenor an alkyl group.

The 17-derivatives of A -3-keto-10methyl-17/8- hydroxy-steroids to beused as starting products in the present process may possess yet othersubstituents elsewhere in the molecule and/or double bonds insofar asthese groups are not sensitive to the present reductive aromatisation.

An important group of starting products are the 17- derivatives of the A-3-keto-17,6-hydroxy-androstadiene, or the l7-alkyl derivatives thereof,which compounds lead to the valuable oestradiol, or the 17-alkylderivatives thereof.

The aromatisation of the starting products of the present inventiontakes place by the known method, consisting in the reaction of such astarting product with at least two atomic equivalents of an alkalimetal, and a polycyclic aromatic compound capable of serving as aradical anion precursor, e.g. biphenyl, naphthalene, methylnaphthalene,phenanthrene or anthracene, in the presence of an ethereal solvent,followed by acidification of the resulting steroidal alkali metal salt,as more fully described in the above cited British patent.

The invention is further illustrated by the following examples:

EXAMPLE I Thirty grams of A -3-keto-l7fl-hydroxy-androstadiene aresuspended in 300 ml. of ethylvinyl-ether, after which slowly, in smallportions, 100 mg. of p-toluene sulphonic acid are added. While thesubstance dissolves the temperature rises to about 25 C. After that thesolution is stirred for minutes. Next the reaction mixture is washedwith 50 ml. of a 10% potassium carbonate solution, after that with wateruntil neutral and finally evaporated to dryness.

2.9 gm. of lithium, 17.5 gm. of diphenylmethane and 37. )2 gm. ofphenanthrene are dissolved in 210 ml. of tetrahydrofuran in nitrogenatmosphere. The reaction mixture is refluxed and after the appearance ofa bluishgreen colour a solution of the above-mentioned residue in 150ml. of tetrahydrofuran is added slowly in such a manner that thebluish-green colour is maintained. After that the mixture is stirred forminutes, cooled down to 10 C., after which the lithium compounds aredecomposed by the subsequent addition of 24 ml. of methanol, 10 ml. ofwater and 45 ml. of concentrated hydrochloric acid. After that themixture is refluxed for 10 minutes to split oif the l7-acetal group.Next the mixture is cooled down, the water layer separated and theorganic layer washed with water until neutral.

The aqueous mixtures are extracted with 50 ml. of benzene and the totalorganic layer evaporated to dryness. The residue is boiled twice with300 ml. of hexane and after cooling down to room temperature filteredoff. The residue is dissolved in 500 ml. of boiling benzene, filteredover hyflo, and crystallised. The mother liquor is chromatographed oversilicagel in benzene. The oestradiol is eluated withbenzene-ethylacetate (9:1). Total yield of pure oestradiol 82% byweight=86.3% of the theory, calculated on input A-3-keto-l75-hydroxy-androstadiene.

From the mother liquors and the residue a small quantity of oestradiolmay yet be obtained raising the conversion percentage to 87% byweight=91.5% of the theory.

Comparative examples starting from other 17-derivatives (a) Ten grams ofandrostadienolone are dissolved in 250 ml. of benzene to which ml. ofdihydropyran are added. At normal pressure 50 ml. of benzene aredistilled off. After cooling down to room temperature 1 gm. of p-toluenesulphonic acid is added, after which the mixture is stirred at roomtemperature for 4 hours. Next the benzene solution is extracted with a5% potassium-carbonate solution and next washed with water untilneutral. Next the benzene solution is evaporated to dryness in vacuo.The residue obtained from it is further treated as described in theprevious Example I. From the resulting reaction product no crystallinematter could be obtained. By chromatography 46% by weight=48.5% of thetheory of oestradiol are obtained.

(b) If the pyranyl-ether is prepared as described in Example (a), butfirst purified, before the reductive aromatisation takes place, 45.5% byweight:48% of the theory of oestradiol are obtained calculated on thecharged quantity of androstadienolone.

(c) If in the present conversion the free androstadienolone or a17-ester thereof is taken as starting material, the following yields areobtained:

(1) Androstadienolone: 15% by weight of oestradiol: 17% of the theory.

(2) Androstadienolone-l7-hexahydrobenzoate: 15% by weight of oestradiol.

(3) Androstadienol-17-acetate: 15.4% by weight of oestradio1=16.4% 0fthe theory.

4 EXAMPLE 11 Starting from A -3 keto-l7fi-hydroxy-androstadiene, whichcompound, by the process described in Example I, has been converted intothe l7-acetal, derived from methylvinyl-ether or butylvinyl-ether, afterwhich these compounds have been aromatised reductively in accordancewith Example 1, pure oestradiol is obtained in a yield of 86 or 83% ofthe theory.

From mother liquors and residues small quantities of oestradiol can yetbe recovered.

EXAMPLE III By the process described in Example I the A -3-keto-17fl-hydroxy-androstadiene has been converted into the 17-acetal,derived from ethylvinyl-ether. Next this compound has been converted inaccordance with Example I into oestradiol in a yield of 8l% of thetheory calculated on androstadienolone, in which the phenanthrene hasbeen replaced by an equivalent quantity of biphenyl, however.

EXAMPLE IV Five grams of A -3-ket0-17,8-hydroxy-l7a-mcthylandrostadieneare dissolved in ml. of ethylvinyl-ether, after which 25 mg. ofp-toluene sulphonic acid are added. After slightly heating the mixtureis maintained at room temperature for 45 minutes, after which 10 mg. ofptoluene sulphonic acid are added. If no noticeable reaction occurs, abicarbonate solution is added, the mixture extracted with ether, washedand evaporated to dryness. The thus obtained crude A -3-keto-l7flethoxy[l'-ethoxy]-17a-rne-thyl-androstadiene is next treated further asdescribed in Example I to obtain pure l7a-methyl-oestradiol in a yieldof of the theory.

What is claimed is:

1. In a process for the manufacture of A -3, l7- dihydroxy steroids bytreatment of a A -3-keto-10- methyl-l7fi-hydroxy steroid with an alkalimetal in the presence of a polycyclic aromatic compound and an etherealsolvent, followed by acid conversion of the alkali metal salt of thecorresponding steroid, the improvement which comprises converting thel7fl-hydroxyl group of a A -3-keto-lO-methyl-l7fi-hydroxy-steroid into aderivative selected from the group consisting of a mixed acetal andketal, by the addition to the 17fl-hydroxy-steroid of a vinyl ether ofthe formula:

Y--OCH=CH in which Y is alkyl with l-4 carbon atoms.

3. Process according to claim 1 in which the corresponding derivative ofA -3-keto-l7 8-hydroxy-androstadiene is taken a the starting material.

4. A steroid of the formula:

5 wherein X is alkyl with 1-6 carbon atoms, R is selected LEWIS GOTTS,Primary Examiner.

from the group consisting of hydrogen and lower alkyl, T M MESHBESHERAssistant Examiner and R R and R are selected from the group consistingof hydrogen and lower alkyl. CL

References Cited 0 2 0 397 5 23955 UNITED STATES PATENTS 3,128,2914/1964 Borrevang 260--397.4 3,274,182 9/1966 Dryden et a1. 260-239.55

